The immune correlates of protection against HIV-1 are unknown making rationale design of efficacious, prophylactic and therapeutic vaccines difficult. This proposal will investigate whether induction of Activation- Induced Non-Responsiveness (AINR) in HIV-specific CD8+T cells leads to disease progression in persons chronically infected with HIV-1. Our preliminary data show that chronic infection with HIV-1 leads to the induction of AINR in HIV-specific T cells. Furthermore, individuals who are controlling chronic HIV-1 infection (long term non-progressors, LTNP) possess HIV-specific T cells that are resistant to AINR. Thus, induction of AINR in HIV-specific CD8+ T cells may be the cause of loss of viral control and progression to AIDS. In Aim 1 we will characterize the functional phenotype of AINR CD8+ HIV-specific T cells to determine which effector functions (apart from proliferative ability) are compromised in the AINR sate using IFN-gamma ELISpot, polychromatic (11 color) flow cytometry and proteomics technologies. Furthermore, longitudinal analysis of these T cell responses throughout the course of infection will allow us to determine when AINR appears in the context of natural infection and whether appearance of AINR CD8+ T cells correlates with disease progression. In Aim 2, we will determine whether HIV-specific AINR CD8+ T cells are compromised in their ability to prevent viral replication using in vitro infectivity assays. We will ascertain whether the presence of AINR HIV-specific T cells in vivo influences viral evolution by sequencing regions of the autologous virus that correspond to epitopes recognized by AINR CD8+ T cells. In addition, we will attempt to reverse the AINR state and determine if this leads to enhanced control of viral infection. In Aim 3, we will identify factors that contribute to induction of AINR. Since the proposed studies will potentially characterize an immune correlate of protection from HIV-1 disease progression they will have far reaching implications on therapeutic intervention in chronically-infected individuals and rationale design of HIV vaccines.